Protein tertiary motifs

Many examples of recurring domain or motif structures are available, and these reveal that protein tertiary structure is more reliably conserved than primary sequence. The comparison of protein structures can thus provide much information about evolution. Proteins with significant primary sequence similarity, and/or with demonstrably similar structure and function, are said to be in the same protein family. A strong evolutionary relationship is usually evident within a protein family. For example, the globin family has many different proteins with both structural and sequence similarity to myoglobin (as seen in the proteins used as examples in Box 4-4 and again in the next chapter). Two or more families with little primary sequence similarity sometimes make use of the same major structural... 

Most work on amphiphilic conjugates to date is based either on simple a-helix-fotming polypeptides or on complex pro-teins/enzymes. Work on biomolecular building blocks that fall between the two aforementioned groups, such as the coiled-coil protein tertiary stmctural motif, has been lim-ited. " Recendy, a heterodimer coiled-coil was used to noncovalendy link PEG and PS blocks and the resultant amphiphilic PEG-peptide-PS triblock copolymer assembled into thermoresponsive micellar assemblies in aqueous solution that transformed from rodlike micelles to spherical micelles upon heating, as depiaed in Figure 10(b). ... 

For example, a polypeptide is synthesized as a linear polymer derived from the 20 natural amino acids by translation of a nucleotide sequence present in a messenger RNA (mRNA). The mature protein exists as a weU-defined three-dimensional stmcture. The information necessary to specify the final (tertiary) stmcture of the protein is present in the molecule itself, in the form of the specific sequence of amino acids that form the protein (57). This information is used in the form of myriad noncovalent interactions (such as those in Table 1) that first form relatively simple local stmctural motifs (helix... 

Fig. 5. Protein folding. The unfolded polypeptide chain coUapses and assembles to form simple stmctural motifs such as -sheets and a-hehces by nucleation-condensation mechanisms involving the formation of hydrogen bonds and van der Waal s interactions. Small proteins (eg, chymotrypsin inhibitor 2) attain their final (tertiary) stmcture in this way. Larger proteins and multiple protein assembhes aggregate by recognition and docking of multiple domains (eg, -barrels, a-helix bundles), often displaying positive cooperativity. Many noncovalent interactions, including hydrogen bonding, van der Waal s and electrostatic interactions, and the hydrophobic effect are exploited to create the final, compact protein assembly. Further stmctural...

RNA structures, compared to the helical motifs that dominate DNA, are quite diverse, assuming various loop conformations in addition to helical structures. This diversity allows RNA molecules to assume a wide variety of tertiary structures with many biological functions beyond the storage and propagation of the genetic code. Examples include transfer RNA, which is involved in the translation of mRNA into proteins, the RNA components of ribosomes, the translation machinery, and catalytic RNA molecules. In addition, it is now known that secondary and tertiary elements of mRNA can act to regulate the translation of its own primary sequence. Such diversity makes RNA a prime area for the study of structure-function relationships to which computational approaches can make a significant contribution. 

Several motifs usually combine to form compact globular structures, which are called domains. In this book we will use the term tertiary structure as a common term both for the way motifs are arranged into domain structures and for the way a single polypeptide chain folds into one or several domains. In all cases examined so far it has been found that if there is significant amino acid sequence homology in two domains in different proteins, these domains have similar tertiary structures. 

These predictive methods are very useful in many contexts for example, in the design of novel polypeptides for the identification of possible antigenic epitopes, in the analysis of common motifs in sequences that direct proteins into specific organelles (for instance, mitochondria), and to provide starting models for tertiary structure predictions. 

The second mode of toxicity is postulated to involve the direct interaction of the epidithiodiketopiperazine motif with target proteins, forming mixed disulfides with cysteine residues in various proteins. Gliotoxin, for example, has been demonstrated to form a 1 1 covalent complex with alcohol dehydrogenase [13b, 17]. Epidithiodi-ketopiperazines can also catalyze the formation of disulfide bonds between proxi-mally located cysteine residues in proteins such as in creatine kinase [18]. Recently, epidithiodiketopiperazines have also been implicated in a zinc ejection mechanism, whereby the epidisulfide can shuffle disulfide bonds in the CHI domain of proteins, coordinate to the zinc atoms that are essential to the tertiary structure of that domain, and remove the metal cation [12d, 19],... 

The functionalization of folded motifs is based on an understanding of secondary and tertiary structures (Fig. 2) and must take into account the relative positions of the residues, their rotamer populations and possible interactions with residues that do not form part of the site. For example, glutamic acid in position i has a strong propensity for salt-bridge formation, and thus reduced reactivity, if there is a Lys residue available i-4 in the sequence, but the probabihty is much less if the base is i-3 [60]. Fortunately, there is a wealth of structural information on the structural properties of the common amino acids from studies of natural proteins that provides considerable support for the design of new proteins. The naturally occurring amino acids have so far been used to construct reactive sites for catalysis [11-13], metal- and heme-binding sites [14,15,19,21,22] and for the site-selective functionalization of folded proteins [24,25]. 

---